Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning
Authors: Nikolaos Koutsouleris, Christos Pantelis, Dennis Velakoulis, Philip McGuire, Dominic B. Dwyer, Maria-Fernanda Urquijo-Castro, Riya Paul, Sen Dong, David Popovic, Oemer Oeztuerk, Joseph Kambeitz, Raimo K. R. Salokangas, Jarmo Hietala, Alessandro Bertolino, Paolo Brambilla, Rachel Upthegrove, Stephen J. Wood, Rebekka Lencer, Stefan Borgwardt, Carlo Maj, Markus Nöthen, Franziska Degenhardt, Maryna Polyakova, Karsten Mueller, Arno Villringer, Adrian Danek, Klaus Fassbender, Klaus Fliessbach, Holger Jahn, Johannes Kornhuber, Bernhard Landwehrmeyer, Sarah Anderl-Straub, Johannes Prudlo, Matthis Synofzik, Jens Wiltfang, Lina Riedl, Janine Diehl-Schmid, Markus Otto, Eva Meisenzahl, Peter Falkai, Matthias L. Schroeter, Shalaila Haas, Alkomiet Hasan, Claudius Hoff, Ifrah Khanyaree, Aylin Melo, Susanna Muckenhuber-Sternbauer, Yanis Köhler, Ömer Öztürk, Nora Penzel, Adrian Rangnick, Sebastian von Saldern, Moritz Spangemacher, Ana Tupac, Johanna Weiske, Antonia Wosgien, Camilla Krämer, Karsten Blume, Dennis Hedderich, Dominika Julkowski, Nathalie Kaiser, Thorsten Lichtenstein, Ruth Milz, Alexandra Nikolaides, Tanja Pilgram, Mauro Seves, Martina Wassen, Christina Andreou, Laura Egloff, Fabienne Harrisberger, Ulrike Heitz, Claudia Lenz, Letizia Leanza, Amatya Mackintosh, Renata Smieskova, Erich Studerus, Anna Walter, Sonja Widmayer, Chris Day, Sian Lowri Griffiths, Mariam Iqbal, Mirabel Pelton, Pavan Mallikarjun, Alexandra Stainton, Ashleigh Lin, Paris Lalousis, Alexander Denissoff, Anu Ellilä, Tiina From, Markus Heinimaa, Tuula Ilonen, Päivi Jalo, Heikki Laurikainen, Antti Luutonen, Akseli Mäkela, Janina Paju, Henri Pesonen, Reetta-Liina Säilä, Anna Toivonen, Otto Turtonen, Sonja Botterweck, Norman Kluthausen, Gerald Antoch, Julian Caspers, Hans-Jörg Wittsack, Giuseppe Blasi, Giulio Pergola, Grazia Caforio, Leonardo Fazio, Tiziana Quarto, Barbara Gelao, Raffaella Romano, Ileana Andriola, Andrea Falsetti, Marina Barone, Roberta Passiatore, Marina Sangiuliano, Marian Surmann, Olga Bienek, Udo Dannlowski, Ana Beatriz Solana, Manuela Abraham, Timo Schirmer, Adele Ferro, Marta Re, Maurizio Sberna, Armando D’Agostino, Lorenzo Del Fabro, Giampaolo Perna, Maria Nobile, Matteo Balestrieri, Carolina Bonivento, Giuseppe Cabras, Franco Fabbro, Giuseppe Delvecchio, Eleonora  Maggioni, Letizia  Squarcina, Davide Gritti, Maria Gloria Rossetti, Raffaele Ferrari, Dena Hernandez, Michael Nalls, Jonathan Rohrer, Adaikalavan Ramasamy, John Kwok, Carol Dobson-Stone, William Brooks, Peter Schofield, Glenda Halliday, John Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, Nigel Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Diego Albani, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian Mackenzie, Ging-Yuek Hsiung, David Mann, Jordan Grafman, Christopher Morris, Johannes Attems, Ian McKeith, Alan Thomas, Pietro Pietrini, Edward Huey, Eric Wassermann, Atik Baborie, Evelyn Jaros, Michael Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James Rowe, Johannes Schlachetzki, James Uphill, John Collinge, Simon Mead, Vivianna Van Deerlin, Anke Marschhauser, Frank Regenbrecht, Angelika Thoene-Otto, Jannis Gordulla, Tommaso Ballarini, Annerose Engel, Daniele Pino, Dominique Leuthold, Heike Naumann, Murray Grossman, John Q Trojanowski, Julie van der Zee, Christine Van Broeckhofen, Stefano F Cappa, Isabelle Le Ber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E Nielsen, Lena E Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N Rossor, Nick C Fox, Jason D Warren, Maria Grazia Spillantini, Huw R Morris, Patrizia Rizzu, Peter Heutink, Julie S Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, David Knopman, Keith A Josephs, Bradley F Boeve, Joseph E Parisi, William W Seeley, Bruce L Miller, Anna M Karydas, Howard Rosen, John C van Swieten, Elise GP Dopper, Harro Seelaar, Yolande AL Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Thibaud Lebouvier, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew B Singleton, John Hardy, Parastoo Momeni, Henryk Barthel, Semler Elisa, Lombardi Jolina, von Arnim Christine, Oberahauser Felix, Schumacher Kai, Lehmbeck Jan, Maler Juan-Manuel, Richter-Schmidinger Tanja, Hammer-Kaspereit Anke, Oberstein Timo, Müller-Sarnowski Felix, Roßmeier Carola, Ludolph Albert, Kassubek Jan, Schneider Anja, Levin Johannes
Journal: JAMA Psychiatry (2022)

<h3>Importance</h3> The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. <h3>Objective</h3> To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). <h3>Design, Setting, and Participants</h3> This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. <h3>Main Outcomes and Measures</h3> Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. <h3>Results</h3> Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (<i>R</i><sup>2</sup> = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the<i>C9orf72</i>variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (<i>R</i><sup>2</sup> = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. <h3>Conclusions and Relevance</h3> Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.